ZA200603307B - Process for preparing substituted 5-amino-pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines - Google Patents
Process for preparing substituted 5-amino-pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines Download PDFInfo
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- ZA200603307B ZA200603307B ZA200603307A ZA200603307A ZA200603307B ZA 200603307 B ZA200603307 B ZA 200603307B ZA 200603307 A ZA200603307 A ZA 200603307A ZA 200603307 A ZA200603307 A ZA 200603307A ZA 200603307 B ZA200603307 B ZA 200603307B
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- South Africa
- Prior art keywords
- formula
- alkoxy
- alkyl
- compound
- group
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims description 5
- IXECJBAWCMPTMB-UHFFFAOYSA-N NC1=NC2=NN=CC2=C2N=CNN12 Chemical class NC1=NC2=NN=CC2=C2N=CNN12 IXECJBAWCMPTMB-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 84
- -1 -NO 5 Chemical group 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 239000002253 acid Substances 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- 230000008569 process Effects 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 claims description 15
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 150000001913 cyanates Chemical class 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical compound C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 claims description 8
- 230000003197 catalytic effect Effects 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 230000003213 activating effect Effects 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical group COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 5
- OYVQPKXNZSZWKL-UHFFFAOYSA-N (2-methoxyphenyl) cyanate Chemical compound COC1=CC=CC=C1OC#N OYVQPKXNZSZWKL-UHFFFAOYSA-N 0.000 claims description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- RFXSQXFVJCZAMW-UHFFFAOYSA-N (4-methoxyphenyl) cyanate Chemical compound COC1=CC=C(OC#N)C=C1 RFXSQXFVJCZAMW-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 claims description 3
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 239000005977 Ethylene Substances 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000005111 carboxyalkoxy group Chemical group 0.000 claims description 2
- 125000004984 dialkylaminoalkoxy group Chemical group 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- SGACLTVKXIFYLM-UHFFFAOYSA-N (4-phenylphenyl) cyanate Chemical compound C1=CC(OC#N)=CC=C1C1=CC=CC=C1 SGACLTVKXIFYLM-UHFFFAOYSA-N 0.000 claims 2
- 125000005085 alkoxycarbonylalkoxy group Chemical group 0.000 claims 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- 108010039224 Amidophosphoribosyltransferase Proteins 0.000 claims 1
- 101100532065 Arabidopsis thaliana RTM3 gene Proteins 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- 229910006074 SO2NH2 Inorganic materials 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- FWYSBEAFFPBAQU-GFCCVEGCSA-N nodakenetin Chemical compound C1=CC(=O)OC2=C1C=C1C[C@H](C(C)(O)C)OC1=C2 FWYSBEAFFPBAQU-GFCCVEGCSA-N 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000012453 solvate Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- KGIWPGKKIFFMKP-UHFFFAOYSA-N 2-(ethoxymethylidene)-3-hydroxybutanedinitrile Chemical compound CCOC=C(C#N)C(O)C#N KGIWPGKKIFFMKP-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 229940106691 bisphenol a Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 2
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- SKTSVWWOAIAIKI-UHFFFAOYSA-N furan-2-carbohydrazide Chemical compound NNC(=O)C1=CC=CO1 SKTSVWWOAIAIKI-UHFFFAOYSA-N 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- NOIXNOMHHWGUTG-UHFFFAOYSA-N 2-[[4-[4-pyridin-4-yl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline Chemical compound C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C1=NN(CC(F)(F)F)C=C1C1=CC=NC=C1 NOIXNOMHHWGUTG-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241001432959 Chernes Species 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000020897 Formins Human genes 0.000 description 1
- 108091022623 Formins Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- KQFHTDXISQQHKO-UHFFFAOYSA-N cyanic acid 2-methoxyphenol Chemical compound OC#N.COC1=CC=CC=C1O KQFHTDXISQQHKO-UHFFFAOYSA-N 0.000 description 1
- QPJDMGCKMHUXFD-UHFFFAOYSA-N cyanogen chloride Chemical compound ClC#N QPJDMGCKMHUXFD-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000002993 cycloalkylene group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229940093470 ethylene Drugs 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000005945 imidazopyridyl group Chemical group 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- LURSUHVHQZXABT-UHFFFAOYSA-N methanesulfinyl chloride Chemical compound CS(Cl)=O LURSUHVHQZXABT-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- CWHFDTWZHFRTAB-UHFFFAOYSA-N phenyl cyanate Chemical class N#COC1=CC=CC=C1 CWHFDTWZHFRTAB-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003378 silver Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001806 thionaphthenyl group Chemical group 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- General Health & Medical Sciences (AREA)
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Description
PROCESS FOR PREPARING SUB STITUTED 5-AMINO-PYRAZOLO-[4,3-6]-1,2.4-
TRIAZOL ۩J[1,5-cIPYRIMIDINES
The present invention relates to a process for preparing substituted 5-amino- pyrazolo}4,3-e}-1,2,4-triazolo-[1,5-c}pyrimidine compounds having an aminoatkyl substituent at the 7-position.
Substituted 5-amino-pyrazolo 14,3-e]-1,2,4-triazolo-[1 ,5-c]pyrimidine compounds disclosed in WO 01/922-64 are useful as Aza receptor antagonists in the treatment of central nervous system diseases, in particular Parkinson's disease.
WO 01/92264 discloses processes for preparing 5-amino-2-substituted- pyrazolo[4,3-e}-1,2,4-triazolo-[1,5-c]goyrimidines comprising dehydrative rearrangement of hydrazines. Baral diet al, J. Med. Chem, 41, (1998), p. 2126-2133 disclose formation of a 5-amino-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine having a phenylalkyl substituent at the 7-po- sition, wherein the reaction comprises reacting a phenylalkyl-substituted hydrazide with (ethoxymethylene)malonitrile to form a substituted pyrazole. Baraldi et al, [B. Med. Chem., 39, (1996), p. 1164-1171 disclose formation of a 7-substituted 5-aminc-pyrazolo[4,3-€]-1,2,4-triazolo-[1,5-c]pyrimidine by reaction of an alkylated pyrazole with (ethoxymethylene)malonitrile. Both Baraldi et al process use NH.CN to accomplish the final ring closure.
The present invention relatess to a process for preparing compounds having the structural formula
NH,
PNY
Rr "x =N
SVN,
N= or a pharmaceutically acceptable salt or solvate thereof, wherein
R is R'-furanyl, R'-thienyl, R®-pyridyl, R'-pyridyl N-oxide, R'-oxazolyl,
R'-phenyl, R'-pyrrolyl or cycloalkenyl;
X is C2-Cg alkylene; (CH2)m i \
ET
Y is ~N(RICH2CHN(R®)-, -OCH,CHN(R?)-, (CHz)2"NH-, or (CHzh R* and
Z is R5-phenyl, R>phenylalkyl, R>-heteroaryl, diphenylmethyl, R®-C(O)-,
Q
HN. N= . —C—
R.-SO,-, © or phenyl-CH(OHY)-; or when Q is H ,Zis also phenylamino or pyridylamino; or
Z and Y together are
Re= » N R N— .
N=y 10 RQ =~ = R \} Ps =~ N— \ V/
R'is 1 to 3 substituents independently selected from hydrogen, alkyl, -CF3, halogen, —NOz, -NR™R™, alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyt;
R? and R2 are independently selected from the group consisting of hydrogen and alkyl; m and n are independently 2-3;
Qis
N= LG 0m ar
H CN ' OH COCHj.
R* is 1-2 substituentss independently selected from the group consisting of hydrogen and alkyl, or two R* substituents on the same carbon can form =O;
RS is 1 to 5 substitue nts independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, -CN, dialkyl-amino, -CF3, -OCFa, acetyl, -NO,, hydroxyatkoxy, alkoxwalkoxy, dialkoxy-alkoxy, alkoxy-alkoxy-alkoxy, carboxy- alkoxy, alkoxycarbonylalko<y, cycloalkyl-alkoxy, dialkyl-amino-alkoxy, morpholinyl, alkyl-SO-, alkyl-SOz-alkoxy/, tetrahydropyranyloxy, alkylcarbonyi-alkoxy, alkoxycarbonyl, alkylcarboryloxy-alkoxy, -SOzNH;, or phenoxy; or adjacent R® substituents together are —O-CHz-O-, -O-CH,CH,-O-, -O-CF2-O- or -O-CF,CF2-O- and form a ring with the ca¥bon atoms fo which they are attached;
R® is alkyl, R®-phenyi, R®-phenylalkyl, thienyl, pyridyl, cycloalkyl, alkyl-OC(0)-NH-(C1-Ce)alkyi-, dialkyl-aminomethyl, or (~ alky-0"S0 .
R? is 1-2 groups indiependently selected from hydrogen, alkyl, hydroxy, alkoxy, halogen, -CF3 and alkoxy-alkoxy;
R'is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, kaydroxy, alkoxy, -CN, -NHo, alkylamino, dialkylamino, -CF3, -OCF3 and -S(O)o-2alkyl;
R'is H or alkyl; ard
R" is alkyl-C(O)- ox alkyl-SOz; comprising a) reacting the hydroxyl group of a pyrazole of formula il
HN rod
N I with an activating aagent in the presence of a base to obtain a compound of formula Ili
HAN on
By I wherein L is a leav ing group, and coupling the compound of formula Ill with a compound of formula IV
Z-Y-H Iv in the presence of a base to obtain a compound of formula V
H2\ CN
Z—Y=X=N_
N? \Y b) treatirmg the compound of formula V with trialkyl orthoformate in the presence= of a catalytic amount of acid to obtain a compound of forms ula VI
NZ OR
CN
Z-Y—X—N wow wherein BR is alkyl; c¢) condensing the compound of formula V1 with a hydrazide of formraula VII
H.NHN-C(O)-R VII in the presence of an acid to obtain a compound of formula Vil
Ne -R
NY
~
Z-Y—X-N ‘NZ vill and hydrolyzing the compound of formula VII to obtain 2 compound of formula BX
N R
HN YY ied
Z-Y—X—N “N7 IX d) cyclizing the compound of formula IX with a cyanating agent selected from the grougp consisting of cyanates and cyanogen halides in the prese=nce of a base to obtain a compound of formula I. in particular, the invention relates to cyclizing a compound of formulla IX with a cyanating agent to obtain a compound of formula I.
Preferred compounds of formula | prepared by the claimed processs are those wherein R is R®-furanyl, R'-thienyl, R'-pyrrolyl or R™-phenyl, more prefera bly
R'-furanyl. R' #s preferably hydrogen or halogen.
Another group of preferred compounds is that wherein X is ethyl ene. [(CHan
AN
Y is prexferably (CHW R* wherein Q is —N— or ~CH—, with Q preferably being nitroger. Preferably, m and n are each 2, and R*is H.
A prefered definition for Z is R™-phenyl, R®-heteroaryl, R®-C(O)— or R®-80x-.
R® is preferably H, halogen, alkyl, alkoxy, hydroxyalkoxy or alkoxyalkoxxy. Ris preferably R5—phenyl. Especially preferred are compounds wherein Z Bs R°-phenyl and R® is one substituent selected from the group consisting of alkoxy and alkoxyalkoxy- A preferred alkoxy group is methoxy, with alkoxyalkoxy being more preferred, e.g., methoxyethoxy and ethoxyethoxy; methoxyethoxy is ranost preferred.
In step a, preferred embodiments of the process use a compou nd of formula
IV-A: —
Om
HaCO IV-A.
In step b, the preferred trialkyl orthoformate is triethyl orthofonmate.
Preferred embodiments of the process use 2-furoic hydrazide imn step ¢ (formula Vi) , thus preparing compounds of formula | wherein R is 2-furyl.
Prefered reagents for the cyclization in step f are cyanates.
In a p referred aspect, the process of the invention comprises the preparation of compounds of the formulas I-A to I-C: re
NZN-N
OO
H;CO I-A
NHa
Aen © ~~ a dy TY od In N= LB
NZ NN A
HaC RP 30, I \ — o—{ )-N_N N 1I—C in a most preferred aspect, the process of the invention comprises the preparation of a compound of formula I-A comprising: a) reacting the hydroxyl group of a pyrazole of formula li "a LCN
HO-X—N_ PP
N 1] with methanesulfonyl chloride in the presence of a base to obtain a compound of formula lila
HoN “NON
Ne
MsO N a; aand coupling the compound of formula Illa with a compound of formula IVa 0 pam NH ~~ \—/
MeO IVa im the presence of a base to obtain a compound of formuala Va .
HN
~ /\ N oH n— NZ ~~ \_/
MeO Va b) treating the compound of formula Va with trimethyl orthoformate in the presence of a catalytic amount of an acid to obtain a compound of formula Via
Paes
Ng ~ = /\ NC
ATE
Vand /
MeO Via «) condensing the compound of formula Via with a hydrazide of formula Vlla
Ho JN rai 0) Viia :
in the presence of an acid to obtain a compound of formula Villa
SAD da
AO Ne
MeO Villa and hydrolyzing the compound of formula Villa to obtain a compoundl of formula IXa .N
Ha
OO
MeO iXa d) cyclizing the compound of formula 1Xa with a cyanating agent selected from the group consisting of cyanates and cyanogen halides in the preserce of a base.
Starting materials of formula Il are known in the art (see, for example, Baraldi et al, J. Med. Chern., 39, (1996), p 1165).
In step a, thwe hydroxyl group on the compound of formula Il is reacted with an activating agent comprising a leaving group, L, wherein L is an optionally smbstituted alkylsulfonyl- or arylsulfonyl- group. When L is a sulfonyl group such as methanesulfonyl, Erifluoromethanesulfonyl, ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyi, p-bromobenzenesulfonyl or m-nitrobenzene-sulfonyl, typically the
L-containing activating agent is an L-halide, e.g., methansulfonyl chloride. A preferred leaving group is methanesuifonyl.
The reactiosn is carried out in a non-protic organic solvent such as CHiCN at a temperature of ab-out -20°C to about 0°C, most preferably at about 0°C. A bout 1-2, preferably about 1-1.5 equivalents of activating reagent are used, and abosut 1-2, preferably about 4-1.5 equivalents of an organic base such as diisopropyleathyl amine.
The activated connpound of formula Ill is not isolated.
The compound of formula Ii is coupled with an amine of formula IV. The reaction is carried out in the presence of an inorganic base such as NaOHE or K2CO,,
at a temperature range of -50°C to about 150°C, preferably at about -20°C to about 0°C, most preferab ly at about -10°C. About 1-2 equivalents of base are u sed.
In step b, thee amino substituent on the compound of formula V is converted to the imidate by treatment with 1-10 equivalents of a trialkyl orthoformate irs a non- protic organic solveant such as toluene at reflux temperature in the presersce of a catalytic amount off acid (e.g., about 1 mol %). Any organic or inorganic acid can be used, but a preferred acid is p-tolunensulfonic acid. A preferred trialkyl o-rthoformate is trimethyl orthofosrmate.
The imidate of formula VI is then condensed with a hydrazide of fomula Vil in step c. The reaction Is carried out in an organic solvent such as toluene ata temperature ranges of about -20°C to about 110°C in the presence of 1-2 equivalents of an acid such ass isobutyric acid.
The compound of formula Vill is then hydrolysed under acidic comditions to form the ring-opened compound of formula IX. The acid can be a mineral acid or an alkyl or aryl sulforic acid; the concentration of acid is not critical, but is preferably at 2.5%. The reaction is carried out at temperature range of about room temperature to about 110°C.
In step d, the compound of formula IX is cyclized by treatment with a cyanating agent selected from the group consisting of cyanates and cyanogen hal3des to obtain a compound of formula |. The reaction is conducted in an organic solvent such as
CH3CN or tetrahydrofuran (THF) at a ratio of 4-20 wiv, preferably about &wiv, optionally in the presence of water (0 to 30% v/v, preferably about 10%. An inorganic base (e.g, Na;CO3, NaHCO3, KHCO3, NaOH, KOH, K3POs, K=HPO.,
NasPO,, Na,HPO.) or organic base (e.g., trialkylamine) is added a ratio= of about 0.2 to 0.5 equivalents. The reaction is carried out at a temperature of abount 35°C to reflux, preferably- about 53°C to about 58°C. 1-2 equivalents of the cyamating agent are used, wherei n the cyanating agent is a cyanate or a cyanogen halicle. Cyanates (i.e., compoundss of the formula Ar-OCN, wherein Ar is an optionally substituted aromatic moiety are exemplified by substituted phenyl cyanates such aas 2-methoxypheny~! cyanate, 4-methoxyphenyl cyanate, 4-phenylphenyl c=yanate and bisphenol A cyarate. Cyanogen halides are exemplified by cyanogen Eoromide and cyanogen chloride. Cyanates are preferred, with 2-methoxyphenyl cya nate being most preferred. The reaction is quenched by the addition of an aqueows solution of an inorganic base (e.g., Na;COs, NaHCO, KHCO3, NaOH, KOH, KaPOs, K2HPO4,
NazPO4, NasHPO,).
The present process provides an advantage over the procedures previously reported in the art. Known processes used highly toxic and corrosive NH2CN to cyclize the ring, while the present process uses a cyanating agent such as a cyanate (e.9., 2-methoxyphenyt cyanate) or @ cyanogen halide (e.g., cyanogen bromide).
Furthermore, the preferred cyanatin g agents, cyanates, are preferable to the relatively more toxic cyanogen halides. Also, the temperature range for conducting the second part of step a of this invention is about 150°C lower than that used in literature preparations. The present inventiors therefore, allows for large scale production and high yields using milder conditions.
As used herein, "alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 6 carbon atoms in the chain.
Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain- Alkylene, referring to a divalent alkyt group, similarly refers to straight or branched chains. rAlkoxy" means an alkyl-O- -group in which the alkyl group is as previously described, unless otherwise noted_ Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxcy, iSOpropoxy, n-butoxy and heptoxy. The bond to the parent moiety is through the ether oxygen. "Cycloalkyl” means a non-a romatic ring system comprising about 3 to about 6 carbon atoms. Non-limiting exampsles of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl and cyclohexyl, and the like. Cycloalkylene refers to a divalent cycloalkyl group. Cycloallkkenyl refers to a C4-Ce cycloalkyl! ring comprising one double bond. “Heteroaryl” means a single ring, bicyclic or benzofused heteroaromatic group of 5 to 10 atoms comprised of 2 to 9 carbon atoms and 1 to 4 heteroatoms independently selected from the garoup consisting of N, O and S, provided that the rings do not include adjacent oxygen and/or sulfur atoms. N-oxides of the ring nitrogens are also included. Exarwples of single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, fuiranyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, theiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl. Examples of bicyclic hetercaaryl groups are naphthyridyl (eg.,1,50r 1,7), imidazopyridyl, pyrido[2,3Jimidazolyl.. pyridopyrimidinyl and 7-azaindolyl. Examples of benzofused heteroaryl groups are in dolyl, quinolyl, isoquinolyl, phthalazinyl, benzothienyl (i.e., thionaphthenyl), beenzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. All positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyt and 4-pyridyl. R5-substituted heteroaryl refers to such groups wherein substitutable ring carbon atoms have a substituent as defined above. "Alkyithio” means an alkyl-S— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methyithio, ethyithio, and i-propyithio. The bond to the parent moiety is through the sulfur. "Alkylsulfonyl” means an alkyi-S(O2) group. The bond to the parent moiety is through the sulfonyl. "Alkylsulfinyl” means an alky/i-S(O)- group. The bond to the parent moiety is through the sulfinyl. “Carbonyl” means a —C(O)- moiety, e.g., alkoxycarbonyl refers to an alkoxy-
C(0)- group (i.e., alkyt-O-C(O)-). “Acetyl” means —C(O)CHa.
Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation. , for example when one or more solvent molecules are incorporated in the crystal latti ce of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methhanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H 20.
Certain compounds of the Invention may exist in different stereoisomeric formss (e.g., enantiomers, diastereoisom ers and atropisomers). The invention contemplates all such stereoisomers both in puwe form and in mixture, including racemic mixtures.
Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxy! group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylgiu camine and the like.
Certain basic compounds also form pha_rmaceutically acceptable salts, e.g., acid addition salts. For example, pyrido-nitrogeen atoms may form salts with strong acid, while compounds having basic substituerts such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric , oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesuiifonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms maay be regenerated by treating the salt with a suitable dilute aqueous base solution s uch as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and baase salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intencled to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponeding compounds for purposes of the invention.
Following are descriptions of the prepaaration of compound I-A using the claimed process.
The following abbreviations are used iin the specification and claims: Ms (methylsulfonyl); Me (methyl); Et (ethyl); LOD (loss on drying); DMAP (4- dimtheylamino-pyridine); and DMSO (dimethayl sulfoxide).
Example 1
Ie
NZ N-N
OO
H3CO
Step a:
HN HN o ace
AT | OT | ed —
HO N mso—/ N° + MeO Va n ia or /\ N _ aan ud N
MeO Va
To a mixture of compound li (200.0 g, 1.0 eq.) and diisopropylethyl amine (280 ml, 1.2 eq.) in CH3CN (600 mi) at °C was slowly added CH3SOCl (112 ml, 1.1 eq.). After the addition was complete, NiaOH (25%, 250 ml) was added at 5°C followed by a solution of compound IVa (34.2g, 1.1eq.) in water (600ml). The reaction mixture was refluxed for 6 h, amd then concentrated to a volume of 800 mi to remove CH;CN. Water (1.2 1) was addexd to the reaction mixture and the batch was cooled to 22°C. The batch was filtered and washed the wet cake with water (600 mi), and dried in a vacuum at 65°C for 24 h. A yellow product was obtained (ca. 415g). "HNMR (CDCl): 7.52 (s, 1H), 6.95 (s, 4H), 5.89 (s, 2H), 4.18 (m, 2H), 4.06 (m, 2H), 3.78 (m, 2H), 3.47 (s, 3H), 3.11 (m, 4H), 2.83 (Mm, 2H), 2.72 (m, 4H).
Step b:
Pa
Ne CN - od 3 ‘sl ve ad ~~ i
A mixture of compound Va (150.0 g, 1.0 eq.), trimethyl orthoformate (120 ml, 2.6 eq.) and a catalytic amount of p-tolmenesulfonic acid in toluene (1.2 1) was heated to a temperature between 105 and 115°C. The reaction mixture was slowly concentrated to 520 ml. The reaction rnixture was then cooled to 15 to 25°C and heptane (1.6 I) was added to complete the precipitation. The batch was filtered, washed with heptane and dried in a va cuum oven at 20 to 30 °C for about 24 h to a
LOD < 0.5%. A light gray product was obtained (ca. 160.8 g).
Mass spectrum: M+1= 413. "HNMR (DMSO): 8.55 (s, 1H), 7.90 (s, 1H), 6.80 (m, 4H), 4.15 (m, 2H), 4.00 (m, 2H), 3.95 (-s, 3H), 3.65 (m, 2H), 3.30 (s, 3H), 2.94 (bs,
~ 13 - 4H), 2.70 (bs, 2H), 2.55 (bs, 4H). BCNMR (DMSO): 1625, 162.4, 150.4, 141.4, 117.6, 115.3, 114.8, 79.7, 70.9, 67.5, 68.5, 56.9, 55.0, 53.0, 49.7, 45.3.
Alternate Step b: : a va pasts av
MeG Vib
A mixture of compound Va (300.0 g, 1.0 eq.), triesthyl orthoformate (280 ml, 2.6 eq.) and a catalytic amount of p-toluenesulfonic acid (3=.0 g) in toluene (1.8 [ was heated to a temperature between 105 and 115°C. The= reaction mixture was slowly concentrated to 1000 ml. The reaction mixture was thesn cooled to 15 to 25°C and heptane (2.1 1) was added to complete the precipitation. The batch was filtered, washed with heptane and dried in a vacuum oven at 2@ to 30 °C forabout24htoa
LOD < 0.5%. A light gray product, Vib, was obtained (ca. 301.2 g).
Mass Spectrum: M+1 = 427. THNMR(DMSO): 8.50 (S , 1H), 7.92 (8S, 1H), 6.81 (m, 4H), 4.35 (m, 2H), 4.10 (t, 2H), 3.99 (m 2H), 3.60 (m, 2H), 3.30 (s, 3H), 2.90 (bs, 4H), 2.50 (m, 4H), 2.70 (t, 2 H), 1.38 (¢, 3H). *CNMR (DMSSO): 162.1, 152.4, 150.6, 145.8, 141.4, 117.6, 115.3, 114.9, 79.770.9, 67.4, 64.71, 58.5, 56.9, 53.0, 49.7,454, 14.2.
Steps c: hat
H \ 1. Isobutyric acid — oY N
Via + wi Ae pig oO Lg vila © 2.110°c MeO Villa lla | i. 4D = oO Me HCl
MeO IXa
Compound Vla (100 g, 1.0 eq.), compound Vila (2-furoic hydrazide) (28.8 g, 0.97 eq.), toluene (400 ml), and isobutyric acid (23 mH, 1.0 eq.) were combined and the reaction mixture was heated to 50°C and stirred feor over 4 h. The reaction mixture was distilled off to about 300 ml at 50°C. The reaction mixture was heated to 110°C, azeotropic distillation was done to remove thes water generated during the reaction, and then the mbxure was stirred at 110-11 55°C for over 4 h. After cooling to 25°C, the reaction mixture was added to 4.1% HCl solution (450 ml) and heated to reflux. The reaction mixture was stirred at reflux for over 2 h, and then cooled to 25°C. The reaction mixture was settled and the aqu eous layer was separated from the organic layer. The aqueous layer was heated to= 50°C and the pH adjusted to between 1.8 and 2.8. After pH adjustment, the aqueous layer was stirred at 50°C for min, and then slowly cooled to 0°C for over 2 h. The aqueous layer was stirred at 0°C for 1 h to complete the precipitation. The solid ~was filtered and washed with water (250 ml). The product was dried in a vacuum oven at 75-80°C. The product was isolated as a mono-HCI salt and the yield was —110g (82%).
MS: m/z 479, 463, 447, 433, 419, 298, 286, 285, 2.72, 263, 240, 247, 243, 235, 229, 216, 206, 194, 191. 'H NMR (DMSO-de): 58.03 (s , 1H); 7.9 (d, 1H); 7.35 (d, 1H); 7.1 (m, 2H); 6.9 (m, 2H); 6.7 (m, 1H); 4.6 (m, 2H); 4.05- (m, 2H); 3.6 (m, 4H); 3.5 (broad, 6H); 3.3 (s, 3H); 2.5 (m, 2H)
Alternatively, an equivalent amount of comp ound Vib can be substituted for compound Vla to obtain compound Xa.
Step d:
To a mixture of compound Xa (100.0 g, 1.0 eq.) amd KHCOs (40 g, 1.5 eq.) in CH3CN (500 ml) and water (10m) at a temperature between 53 and 58°C was slowly added 2-methoxyphenol cyanate (39.0 g, 1.35 eq.). The reaction mixture was agitated at a temperature between 53 and 58°C for 1 h. Upon completion of the reaction, a 10%
NaOH aqueous solution (200 ml) was added to queench the reaction. The batch was then cooled to a temperature between 20 and 25°«C, and filtered. The cake was washed with water (400ml) and CN3CN (400ml) ard dried in a vacuum oven at 65 to 75°C for about 12 h. A white product was obtained (ca. 91.0g) with about 95% yield.
Mass spectrum: M+1= 504. HNMR (DMSO). 8.387 (s, 1H), 8.13 (bs, 2H), 7.95 (m, 1H), 7.18 (m, 1H), 6.78 (m, 4H), 6.70 (m, 1H), 4.3 8 (m, 2H), 4.93(m, 2H), 3.56 (Mm, 2H), 3.37 (s, 3H), 2.90 (m, 4H), 2.80 (m, 2H), 2.55 (m, 4H), 2.45 (m, 2H).
Example 2 re
NNN
_ SE
OO
HLCO
To a mixture of compound Xa (Example 1, step c) (5%0.0 9, 1.0 eq.) and DMAP (24.0 g, 2.0 eq.) in CH3CN (850 ml) at a temperature between 75 and 85°C was slowly amdded a solution of BrCN (15.0 g, 1.3 eq.) in CH3CN «150.0 ml). The reaction mixture was refluxed for another 3 h. The reaction was cooled to 25°C, and 10%
NaOH ssolution (500 ml) was added to quench the reaction. The batch was filtered, washed with water and dried in a vacuum oven at 65 to 75°C for about 24 h. A light gray product was obtained (ca. 32.0g). .
Mass sspectrum: M+1= 504. "HNMR (DMSO): 8.37 (s, 1H), 8.13 (bs, 2H), 7.95 (m, 1H), 7. 18 (m, 1H), 6.78 (m, 4H), 6.70 (m, 1H), 4.38 (m, 2H), 4.93(m, 2H), 3.56 (m, 2H), 3.337 (s, 3H), 2.90 (m, 4H), 2.80 (m, 2H), 2.55 (m, 4H), 2.45 (m, 2H).
Example 3
Ire
NZ N-N
SS
OO
H3;CO
To a mixture of compound IXa (Example 1, step c) ( 100.0 g, 1.0 eq.) in THF {500 nl), water (100 ml) and NaOH (50%, 17.0 g) at a tempoerature between 60 and 70°C wwas slowly added a solution of bisphenol-A cyanate ( 30.0 g, 1.1 eq.) in THF (125.0 ml). The reaction mixture was refluxed for another 1 .5 h. The reaction mixture was cooled to 25°C, filtered, washed with water and dried i n a vacuum oven at 65 to 75°C faor about 24 h. A light gray product was obtained (cam. 88.0 g).
Mass spectrum: M+1= 504. "HNMR (DMSO): 8.37 (s, 1 H), 8.13 (bs, 2H), 7.95 (m, 1H), 77.18 (m, 1H), 6.78 (m, 4H), 6.70 (m, 1H), 4.38 (m, 2H), 4.93(m, 2H), 3.56 (m, 2H), 3 .37 (s, 3H), 2.90 (m, 4H), 2.80 (m, 2H), 2.55 (m, 4H) , 2.45 (m, 2H).
While the present invention has been described in conjunction with the specific embocliments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifi=cations and variations are intended to fall within the sspirit and scope of the presert invention.
Claims (16)
1. A process for preparing compounds havirg the structural formula NHz NANI ah Z-Y—X—N N= I or a pharmaceutically acceptable salt thereof , wherein R is R'-furanyl, R'-thienyl, R'-pyridyl, R'—pyridy} N-oxide, R"-oxazolyl, R'*-phenyl, R'-pyrrolyt or cycloalkenyl; X is C,-Cg alkylene; (CH) —a E Y is =N(RYCH2CHN(R®)-, -OCH2CHN(R?)-, -(CHa)-NH-, or (Crs : and Z is R®phenyl, R%-phenylalkyl, R>heteroaryl, diphenylmethyl, R®-C(O)-, Q HN, N= —C— ~ R%-Ss0,-, © or phenyl-CH(OH)-; orwherny Qis H ,Zis also phenylamino or ] pyridylamino; : or Z and Y together are 9 ’ N . N— N= R10 RE (SWC. OC or Rm R'is 1 to 3 substituents independently selected from hydrogen, alkyl, -CF3, halogen, ~NO2, -NR'2R™, alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl; R? and R? are independently selected from the group consisting of hydrogen and alkyl; m and n are independently 2-3; Qis AMENDE D SHEET ded de H CN ' OH COCHjs
R* is 1-2 substituents independently selected fron the group consisting of hydrogen and alkyl, or two R* substituents on the same carbon can form =O;
Ris 1 to 5 substituents independently selected fr-om the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, -CN, dialkyl-aamino, -CF3, -OCF3, acetyl, -NO 5, hydroxyalkoxy, alkoxyalkoxy, dialkoxy-alkoxy, alkomxy-alkoxy-alkoxy, carboxy- alko xy, alkoxycarbonylalkoxy, cycloalkyl-alkoxy, dialkyl-aamino-alkoxy, morpholinyl, alky 1-SO.-, alkyl-SOz-alkoxy, tetrahydropyranyloxy, alkylecarbonyl-atkoxy, alkosxycarbonyl, alkylcarbonyloxy-alkoxy, -SO2NHa, or pienoxy; or adjacent R® substituents together are —0-CHz-0-, -O-CH,CH2-0O-, ~O-CF2-O- or -0-CF,CF>-0- and form a ring with the carbon atoms to which they are attached;
RS is alkyl, R®-phenyl, R>-phenylalkyl, thienyl, pyridyl, cycloalkyl, alkyl-OC(O)-NH-(C4-Cs)alkyl-, dialkyl-aminomethyl, or
(= alkyl 0 :
R® is 1-2 groups independently selected from hydrogen, alkyl, hydroxy, alkoxy, halogen, -CF3 and alkoxy-alkoxy;
R' is 1 to 5 substituents independently selected from the group consisting of hyd rogen, halogen, alkyl, hydroxy, alkoxy, -CN, -NH,, al kylamino, dialkylamino, -CFs3, -OCF; and -S(O)o-zalkyt;
R'is H or alkyl; and
R™ is alkyl-C(OY- or alkyl-SOx-; comprising a) reacting the hydroxyl group of a pyrazole of fomrmula Il
HN con ey { in with an activating agent in the presence of a basee to obtain a compound of formula Il HN oN xd 1 wherein L is a leaving group, and coupling the compound of formula Ill with a cosmpound of formula \Y) Z-Y-H \' in the presence of a base to obtain a compound off formula V HaN CN Z2=Y=X—N_ NZ / b) treating the compound of formula V with trialky=1 orthoformate in the presence of a catalytic amount of an acid to obtaim a compound of formula Vi NZ OR =~" Z=Y=X—N, NW wherein R’ is alky}; c¢) condensing the compound of formula Vi with a hydrazide of formula VII
H.NHN-C(O)-R VII in the presence of an acid to obtain a compound of formula Vili NR NY oll . Z-Y—X-N ‘NZ Vili and hydrolyzing the compound of formula Vill to obtain a compound of formula IX NR HN YY ied Z—-Y—X—N N IX d) cyclizing the compound of formula IX with a cyanating agent selected from the group consisting of cyanates and cyanogen halides in the presence of a base.
2. The process of claim 1 for preparing compounds of formula | wherein: R is Rfuranyl, R'-thienyl, R'-pyrrolyl or R"-phenyl; R'is hydrogen or halogen; Xis
(CH / \ TA NN . (CHAS 4 X Lo —N— Ale. . 5 5 ethylene; Yis 2h "R* wherein Q is or ~CH—; Z is R>-phenyl, R™- heteroaryl, RS-C(0)- or R-80,-; and R® is R°-phenyl.
3. The process of claim 2 wherein R is R'-furanyt; R' is h-ydrogen or halogen; Q is i” m amd n are each 2; Ris H; Zis R>-phenyl; and R= is one substituent selected fron the group consisting of alkoxy and alkoxyalkoxy~.
4, The p rocess of claim 2 wherein L is an optionally subsEituted alkylsulfonyl- or arylsulfonyl- group.
5. The perocess of claim 4 wherein Lis a alkylsulfonyl- or =arylsulfonyl- group , selected frorm the group consisting of methanesulfonyl, trifluo romethanesulfonyl, ethanesuifornyl, benzenesulfonyl, p-toluenesulfonyl, p-bromotoenzenesulfonyl and m- nitrobenzenseesulfonyl.
6. The process of claim 5 wherein L is methanesulfonyl.
7. The process of claim 1, step b, wherein the triatky! ortBhoformate is trimethyl orthoformat e.
8. The pprocess of claim 1 wherein the cyanating agent ir step d is a cyanate.
9. The “process of claim 8 wherein the cyanate is selectexd from the group consisting Of 2-methoxyphenyl cyanate, 4-methoxyphenyl cy=anate, 4-phenyiphenyl , cyanate ansd bisphenol A cyanate.
10. The process of claim 9 wherein the cyanate is 2-metihoxyphenyl cyanate.
11. The process of claim 1 for preparing a compound of formula I-A
N¥ NA 7 \ raat am pO H3CO I-A comprising a) reacting the hydroxyl group of a pyrazole of formula Il " CN HO-X—N_ PF N i with rmethanesulfony! chloride in the presence of a base to olotain a compound of formula llla HoN “NON Ne MsO N lla; and coupling the compound of formula fila with a compound of formula IVa 0 YN NH ~~ \/ MeO IVa in thes presence of a base to obtain a compound of formula Wa HN ~ \ N o—~ In Nn— NT ~~ \—/ MeO w/a b) treating the compound of formula Va with trimethyl orthofformate in the pressence of a catalytic amount of an acid to obtain a compo und of formula Via Je N’ ~r™ N OO ~~ \—/ MeO Via c) condensing the compound of formula Via with a hydrazicie of formula Via HJ \ 0] Vila
. : PCT/US200=4/035472 in the presence of &an acid to obtain a compound of formula Villa AD ~ N ~\ N od H+ — N — nn / MeO Villa and hydrolyzing thee compound of formula Villa to obtain a compound of formula 1Xa ML) HN HoN AT N o—{ Nn NZ — n/ MeO Xa d) cyclizing the compound of formula 1Xa with a cyanating agent sel ected from the group conssisting of cyanates and cyanogen halides in the presence of a base.
12. The process of cl aim 11 wherein the cyanating agent is a cyanate selected from the group consisting of 2-methoxyphenyl cyanate, 4-methoxyphenyl cyanate, 4-phenylphenyl cyanate and bisphenol A cyanate.
13. A process for pre=paring a compound of formula N ‘ad NN R SS =N NG N= or a pharmaceutically acceptable salt thereof, wherein Ris R'-furanyl, RR -thienyl, R'-pyridy}, R'-pyridyl N-oxide, R'-oxazol=y}, R"-phenyl, R'-pyrrolyl «or cycloalkenyl; X is C2-C; alkyle ne; CCH2)m / \ Y is “N(RIICH2CHZN(RY)-, -OCH,CHaN(R?)-, (CHa) NH, or LEH RE, and AMENDED SHEET
Z is R%-phenyl, R®phenylalkyl, R>heteroaryl, diphenylmethyl, R®-C(O)-, Q HN, N— —o
I . R%-80,, © or phenyl-CH(OH)-; or when Q is H |, Z is also phenylamino or pyridylamino; or Z and Y together are 9 ’ N . N— oo! Oy Fe oN R'is 1 to 3 substituents independently selected from hydrogen, alkyl, -CFa, halogen, -NO2, -NR'?R™3, alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl; R? and R® are ind ependently selected from the group consisting of hydrogen and alkyl; m and n are independently 2-3; Qis Ra eo a
[3] CN ’' OH COCH; . R* is 1-2 substitu ents independently selected from the group consisting of hydrogen and alkyl, or two R* substituents on the same carbon can form =O; RY is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, -CN, dialkyl-amino, -CF3, -OCF3, acetyl, -NO,, hydroxyalkoxy, al koxyalkoxy, dialkoxy-alkoxy, alkoxy-alkoxy-alkoxy, carboxy- alkoxy, alkoxycarbonylalkoxy, cycloalkyl-alkoxy, dialkyl-amino-alkoxy, morpholinyl, alkyl-SO2-, alkyl-SOz-al koxy, tetrahydropyranyloxy, alkylcarbonyl-alkoxy, alkoxycarbonyl, alkylcarbonyloxy-alkoxy, -SO2NH2, or phenoxy; or adjacent R® substituents together axe ~0-CHz-0-, -O-CH2CH,-O-, ~0-CF2-O- or -O-CF.CF2>-O- and form a ring with thes carbon atoms to which they are attached; R® is alkyl, R5-phenyl, R>-phenylalkyl, thienyl, pyridyl, cycloalkyl, alkyl-OC(O)-NH-C;-Cg)alkyl-, dialkyl-aminomethyl, or
{~ alky-0"S0 : R® is 1-2 groups independently selected from hydrogen, alkyl, hydroxy, alkoxy, halogen, -CF3 and alkoxy-alkoxy; R™ is 1 to § substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkcoxy, -CN, -NH2, alkylamino, dialkylamino, -CFs3, -OCF3 and -S(O)2alkyl; R'?is H or alkyl; and R" is alkyl-C(O)- or alkyl-SOz-; comprising cyclizing a compound of formula IX nS ied Zo XN, = IX with a cyanating agent selected from the group consisting of cyanates and cyanogen halides in the presence of a base.
14. The process of claim 13 wherein the cyanating agent is a cyanate selected from the group consisting of 2-methoxyphenyl cyanate, 4-methoxyphenyl cyanate, 4-phenylphenyl cyanate and bisphersol A cyanate.
15. The process of claim 13 for pweparing compounds of formula | wherein R is R'-furanyl, R'-thienyl, R'-pyrrolyl or FR"-phenyl; R'is hydrogen or halogen; X is (CH)m I Gl ok othylene; Yis Ch R' whereiinQis “N— or —CH—; Zis R®-phenyl, R°- heteroaryl, R®-C(O)- or R%-80,-; and R® is R*-phenyl.
16. The process of claim 15 wherein R is R"-furanyl; R'is hydrogen or halogen; Q is =; mand n are each 2; R*is H; Z is R®-phenyl; and R® is one substituent selected from the group consisting of alkoxy and atkoxyalkoxy.
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US20110144049A1 (en) * | 2009-10-21 | 2011-06-16 | Serebruany Victor L | Treating Cardiac Arrhythmias, Heart Failure, Peripheral Artery Disease and Stroke with Cyclopentyl-Triazolo-Pyrimidine or Derivative Thereof |
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